tbuckley/cabot-search huggingface dataset:
Bolus versus Continuous Intravenous Delivery of Doxorubicin in Soft-Tissue Sarcomas:<i>Post Hoc</i>Analysis of a Prospective Randomized Trial (SARC021/TH CR-406)
Authors: Lee D. Cranmer, Yao Lu, Rachel S. Heise, Karla V. Ballman, Elizabeth T. Loggers, Seth M. Pollack, Michael J. Wagner, Denise K. Reinke, Patrick Schöffski, William D. Tap
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Continuous intravenous infusion (CIV) of doxorubicin (DOX) versus bolus (BOL) may minimize dose-dependent DOX cardiomyopathy, but it is unclear whether this advantage is evident as employed in typical soft-tissue sarcoma (STS) treatment. The impact of administration mode on adverse events (AE) and efficacy were compared using data from a randomized trial of DOX-based therapy (SARC021/TH CR-406). Experimental Design: In this post hoc analysis, CIV versus BOL was at discretion of the treating physician. Likelihood of AEs, and objective responses were assessed by adjusted logistic regression. Progression-free (PFS) and overall survival (OS) were compared using Kaplan–Meier, log-rank test, and adjusted Cox regression. Results: DOX was administered by BOL to 556 and by CIV to 84 patients. Proportions experiencing hematologic, non-hematologic, or cardiac AEs did not differ by administration mode. Hematologic AEs were associated with age, performance status, and cumulative DOX. Non-hematologic AEs were associated with age, performance status, and cumulative evofosfamide. Cardiac AEs were only associated with cumulative DOX; there was no interaction between DOX dose and delivery mode. PFS and OS were similar (median PFS 6.14 months BOL vs. 6.11 months CIV, P = 0.47; median OS 18.4 months BOL vs. 21.4 months CIV, P = 0.62). PFS, OS, and objective responses were not associated with delivery mode. Conclusions: CIV was not associated with superior outcomes over BOL within DOX dosing limits of SARC021. Cardiac AEs were associated with increasing cumulative DOX dose. While not randomized with respect to DOX delivery mode, the results indicate that continued investigation of AE mitigation strategies is warranted.
Synthetic Lethal Interaction with BCL-XL Blockade Deepens Response to Cetuximab in Patient-Derived Models of Metastatic Colorectal Cancer
Authors: Simonetta M. Leto, Martina Ferri, Francesco Sassi, Eugenia R. Zanella, Francesca Cottino, Valentina Vurchio, Irene Catalano, Alessandro Ferrero, Caterina C. Zingaretti, Caterina Marchiò, Elena Grassi, Livio Trusolino, Andrea Bertotti
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Approximately 20% of patients with RAS wild-type metastatic colorectal cancer (mCRC) experience objective responses to the anti-EGFR antibody cetuximab, but disease eradication is seldom achieved. The extent of tumor shrinkage correlates with long-term outcome. We aimed to find rational combinations that potentiate cetuximab efficacy by disrupting adaptive dependencies on antiapoptotic molecules (BCL2, BCL-XL, MCL1). Experimental Design: Experiments were conducted in patient-derived xenografts (PDX) and organoids (PDXO). Apoptotic priming was analyzed by BH3 profiling. Proapoptotic and antiapoptotic protein complexes were evaluated by co-immunoprecipitation and electroluminescence sandwich assays. The effect of combination therapies was assessed by caspase activation in PDXOs and by monitoring PDX growth. Results: A population trial in 314 PDX cohorts, established from as many patients, identified 46 models (14.6%) with appreciable (&amp;gt;50% tumor shrinkage) but incomplete response to cetuximab. From these models, 14 PDXOs were derived. Cetuximab primed cells for apoptosis, but only concomitant blockade of BCL-XL precipitated cell death. Mechanistically, exposure to cetuximab induced upregulation of the proapoptotic protein BIM and its sequestration by BCL-XL. Inhibition of BCL-XL resulted in displacement of BIM, which was not buffered by MCL1 and thereby became competent to induce apoptosis. In five PDX models, combination of cetuximab and a selective BCL-XL inhibitor triggered apoptosis and led to more pronounced tumor regressions and longer time to relapse after treatment discontinuation than cetuximab alone. Conclusions: In mCRC tumors that respond to cetuximab, antibody treatment confers a synthetic-lethal dependency on BCL-XL. Targeting this dependency unleashes apoptosis and increases the depth of response to cetuximab.
De Novo <scp><i>PACSIN1</i></scp> Gene Variant Found in Childhood Lupus and a Role for <scp>PACSIN1</scp>/<scp>TRAF4</scp> Complex in Toll‐like Receptor 7 Activation
Authors: Chengmei Xie, Haibo Zhou, Vicki Athanasopoulos, Qian Shen, Yaoyuan Zhang, Xiangpeng Meng, Gaetan Burgio, Todor Arsov, Adrian C. Lungu, Pingjing Zhang, Yuting Qin, Jiangyang Ma, Xiaoqian Wu, Xiaoyue Jiang, Huihua Ding, Yao Meng, Nan Shen, Yuke He, Carola G. Vinuesa
Journal: Arthritis & Rheumatology (2023)

Increased Toll-like receptor 7 (TLR-7) signaling leading to the production of type I interferon (IFN) is an important contributor to human systemic lupus erythematosus (SLE). Protein kinase C and casein kinase substrate in neurons 1 (PACSIN1), a molecule that regulates synaptic vesicle recycling, has been linked to TLR-7/TLR-9-mediated type I IFN production in humans and mice, but the underlying mechanism is unknown. We undertook this study to explore the pathogenicity and underlying mechanism of a de novo PACSIN1 missense variant identified in a child with SLE.PACSIN1 Q59K de novo and null variants were introduced into a human plasmacytoid dendritic cell line and into mice using CRISPR/Cas9 editing. The effects of the variants on TLR-7/TLR-9 signaling in human and mouse cells, as well as PACSIN1 messenger RNA and IFN signature in SLE patients, were assessed using real-time polymerase chain reaction and flow cytometry. Mechanisms were investigated using luciferase reporter assays, RNA interference, coimmunoprecipitation, and immunofluorescence.We established that PACSIN1 forms a trimolecular complex with tumor necrosis factor receptor-associated factor 4 (TRAF4) and TRAF6 that is important for the regulation of type I IFN. The Q59K mutation in PACSIN1 augments binding to neural Wiskott-Aldrich syndrome protein while it decreases binding to TRAF4, leading to unrestrained TRAF6-mediated activation of type I IFN. Intriguingly, PACSIN1 Q59K increased TLR-7 but not TLR-9 signaling in human cells, leading to elevated expression of IFNβ and IFN-inducible genes. Untreated SLE patients had high PACSIN1 expression in peripheral blood cells that correlated positively with IFN-related genes. Introduction of the Pacsin1 Q59K mutation into mice caused increased surface TLR-7 and TRAIL expression in B cells.PACSIN1 Q59K increases IFNβ activity through the impairment of TRAF4-mediated inhibition of TLR-7 signaling, possibly contributing to SLE risk.
Novel Titanium Implant: A 3D Multifunction Architecture with Charge‐Trapping and Piezoelectric Self‐Stimulation
Authors: Lei Sun, Xuzhuo Chen, Kun Ma, Ruiguo Chen, Yi Mao, Rui Chao, Hui Wang, Bin Yu, Junfeng Wang, Shanyong Zhang
Journal: Advanced Healthcare Materials (2023)

Implant-associated infection and inflammation are the main causes of implant failure, causing irreversible damage and significantly increasing clinical risks and economic losses. In this study, a 3D multifunctional architecture is constructed that consisted of hierarchical TiO2 nanotubes (NTs) and electrospun polyvinylidene fluoride nanofiber layers on the surface of a titanium implant. The movement of bacteria through the nanofiber layer is facilitated by its appropriate pore sizes and electrostatic interactions to reach the NT layer where the bacteria are killed by positive charge traps. In contrast, the macrophages tend to adhere to the nanofiber layer. The mechanical interactions between the macrophages and piezoelectric nanofibers generate a self-stimulated electric field that regulated an anti-inflammatory phenotype. This study provides a new method for multifunctional implant materials with antibacterial, piezoelectrically self-stimulated anti-inflammatory, and osteointegration properties that are driven by electrical stimulation.
A diagnostic performance study of the 2022 American College of Rheumatology/<scp>EULAR</scp> classification criteria for giant cell arteritis in a cohort of patients presenting with suspected giant cell arteritis
Authors: Andrea K. Hemmig, Markus Aschwanden, Stephan Imfeld, Christoph T. Berger, Thomas Daikeler
Journal: Arthritis & Rheumatology (2023)

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The Genetic Landscape of Familial Pulmonary Fibrosis
Authors: Qi Liu, Yuan Zhou, Joy D. Cogan, Daphne B. Mitchell, Quanhu Sheng, Shilin Zhao, Youhuang Bai, Kristen K. Ciombor, Carleen M. Sabusap, M. Merced Malabanan, Cheryl R. Markin, Katrina Douglas, Guixiao Ding, Nicholas E. Banovich, Deborah A. Nickerson, Elizabeth E. Blue, Michael J. Bamshad, Kevin K. Brown, David A. Schwartz, John A. Phillips, Ruben Martinez-Barricarte, Margaret L. Salisbury, Yu Shyr, James E. Loyd, Jonathan A. Kropski, Timothy S. Blackwell
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale and Objectives: Up to 20% of idiopathic interstitial lung disease is familial, referred to as familial pulmonary fibrosis (FPF). An integrated analysis of FPF genetic risk was performed by comprehensively evaluating for genetic rare variants (RVs) in a large cohort of FPF kindreds. Methods: Whole-exome sequencing and/or candidate gene sequencing from affected individuals in 569 FPF kindreds was performed, followed by cosegregation analysis in large kindreds, gene burden analysis, gene-based risk scoring, cell-type enrichment analysis, and coexpression network construction. Measurements and Main Results: It was found that 14.9–23.4% of genetic risk in kindreds could be explained by RVs in genes previously linked to FPF, predominantly telomere-related genes. New candidate genes were identified in a small number of families—including SYDE1, SERPINB8, GPR87, and NETO1—and tools were developed for evaluation and prioritization of RV-containing genes across kindreds. Several pathways were enriched for RV-containing genes in FPF, including focal adhesion and mitochondrial complex I assembly. By combining single-cell transcriptomics with prioritized candidate genes, expression of RV-containing genes was discovered to be enriched in smooth muscle cells, type II alveolar epithelial cells, and endothelial cells. Conclusions: In the most comprehensive FPF genetic study to date, the prevalence of RVs in known FPF-related genes was defined, and new candidate genes and pathways relevant to FPF were identified. However, new RV-containing genes shared across multiple kindreds were not identified, thereby suggesting that heterogeneous genetic variants involving a variety of genes and pathways mediate genetic risk in most FPF kindreds.
piRNAs regulate a Hedgehog germline-to-soma pro-aging signal
Authors: Cheng Shi, Coleen T. Murphy
Journal: Nature Aging (2023)

Abstract The reproductive system regulates somatic aging through competing anti- and pro-aging signals. Germline removal extends somatic lifespan through conserved pathways including insulin and mammalian target-of-rapamycin signaling, while germline hyperactivity shortens lifespan through unknown mechanisms. Here we show that mating-induced germline hyperactivity downregulates piRNAs, in turn desilencing their targets, including the Hedgehog-like ligand-encoding genes wrt-1 and wrt-10 , ultimately causing somatic collapse and death. Germline-produced Hedgehog signals require PTR-6 and PTR-16 receptors for mating-induced shrinking and death. Our results reveal an unconventional role of the piRNA pathway in transcriptional regulation of Hedgehog signaling and a new role of Hedgehog signaling in the regulation of longevity and somatic maintenance: Hedgehog signaling is controlled by the tunable piRNA pathway to encode the previously unknown germline-to-soma pro-aging signal. Mating-induced piRNA downregulation in the germline and subsequent Hedgehog signaling to the soma enable the animal to tune somatic resource allocation to germline needs, optimizing reproductive timing and survival.
MHC II immunogenicity shapes the neoepitope landscape in human tumors
Authors: Jeong Yeon Kim, Hongui Cha, Kyeonghui Kim, Changhwan Sung, Jinhyeon An, Hyoeun Bang, Hyungjoo Kim, Jin Ok Yang, Suhwan Chang, Incheol Shin, Seung-Jae Noh, Inkyung Shin, Dae-Yeon Cho, Se-Hoon Lee, Jung Kyoon Choi
Journal: Nature Genetics (2023)
A survey of COVID-19 vaccine acceptance across 23 countries in 2022
Authors: Jeffrey V. Lazarus, Katarzyna Wyka, Trenton M. White, Camila A. Picchio, Lawrence O. Gostin, Heidi J. Larson, Kenneth Rabin, Scott C. Ratzan, Adeeba Kamarulzaman, Ayman El-Mohandes
Journal: Nature Medicine (2023)
Multistain deep learning for prediction of prognosis and therapy response in colorectal cancer
Authors: Sebastian Foersch, Christina Glasner, Ann-Christin Woerl, Markus Eckstein, Daniel-Christoph Wagner, Stefan Schulz, Franziska Kellers, Aurélie Fernandez, Konstantina Tserea, Michael Kloth, Arndt Hartmann, Achim Heintz, Wilko Weichert, Wilfried Roth, Carol Geppert, Jakob Nikolas Kather, Moritz Jesinghaus
Journal: Nature Medicine (2023)
Behavioral origin of sound-evoked activity in mouse visual cortex
Authors: Célian Bimbard, Timothy P. H. Sit, Anna Lebedeva, Charu B. Reddy, Kenneth D. Harris, Matteo Carandini
Journal: Nature Neuroscience (2023)

Sensory cortices can be affected by stimuli of multiple modalities and are thus increasingly thought to be multisensory. For instance, primary visual cortex (V1) is influenced not only by images but also by sounds. Here we show that the activity evoked by sounds in V1, measured with Neuropixels probes, is stereotyped across neurons and even across mice. It is independent of projections from auditory cortex and resembles activity evoked in the hippocampal formation, which receives little direct auditory input. Its low-dimensional nature starkly contrasts the high-dimensional code that V1 uses to represent images. Furthermore, this sound-evoked activity can be precisely predicted by small body movements that are elicited by each sound and are stereotyped across trials and mice. Thus, neural activity that is apparently multisensory may simply arise from low-dimensional signals associated with internal state and behavior.
Single-cell transcriptomic analysis of endometriosis
Authors: Marcos A. S. Fonseca, Marcela Haro, Kelly N. Wright, Xianzhi Lin, Forough Abbasi, Jennifer Sun, Lourdes Hernandez, Natasha L. Orr, Jooyoon Hong, Yunhee Choi-Kuaea, Horacio M. Maluf, Bonnie L. Balzer, Aaron Fishburn, Ryan Hickey, Ilana Cass, Helen S. Goodridge, Mireille Truong, Yemin Wang, Margareta D. Pisarska, Huy Q. Dinh, Amal EL-Naggar, David G. Huntsman, Michael S. Anglesio, Marc T. Goodman, Fabiola Medeiros, Matthew Siedhoff, Kate Lawrenson
Journal: Nature Genetics (2023)
Full protection from SARS-CoV-2 brain infection and damage in susceptible transgenic mice conferred by MVA-CoV2-S vaccine candidate
Authors: Javier Villadiego, Juan García-Arriaza, Reposo Ramírez-Lorca, Roberto García-Swinburn, Daniel Cabello-Rivera, Alicia E. Rosales-Nieves, María I. Álvarez-Vergara, Fernando Cala-Fernández, Ernesto García-Roldán, Juan L. López-Ogáyar, Carmen Zamora, David Astorgano, Guillermo Albericio, Patricia Pérez, Ana M. Muñoz-Cabello, Alberto Pascual, Mariano Esteban, José López-Barneo, Juan José Toledo-Aral
Journal: Nature Neuroscience (2023)
Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome
Authors: Erin Parry, Ignaty Leshchiner, Romain Guièze, Connor Johnson, Eugen Tausch, Sameer Parikh, Camilla Lemvigh, Julien Broséus, Sébastien Hergalant, Conor Messer, Filippo Utro, Chaya Levovitz, Kahn Rhrissorrakrai, Liang Li, Daniel Rosebrock, Shanye Yin, Stephanie Deng, Kara Slowik, Raquel Jacobs, Teddy Huang, Shuqiang Li, Geoff Fell, Robert Redd, Ziao Lin, Binyamin Knisbacher, Dimitri Livitz, Christof Schneider, Neil Ruthen, Liudmila Elagina, Amaro Taylor-Weiner, Bria Persaud, Aina Martinez, Stacey Fernandes, Noelia Purroy, Annabelle Anandappa, Jialin Ma, Julian Hess, Laura Rassenti, Thomas Kipps, Nitin Jain, William Wierda, Florence Cymbalista, Pierre Feugier, Neil Kay, Kenneth Livak, Brian Danysh, Chip Stewart, Donna Neuberg, Matthew Davids, Jennifer Brown, Laxmi Parida, Stephan Stilgenbauer, Gad Getz, Catherine Wu
Journal: Nature Medicine (2023)
Multimodal single-cell and whole-genome sequencing of small, frozen clinical specimens
Authors: Yiping Wang, Joy Linyue Fan, Johannes C. Melms, Amit Dipak Amin, Yohanna Georgis, Irving Barrera, Patricia Ho, Somnath Tagore, Gabriel Abril-Rodríguez, Siyu He, Yinuo Jin, Jana Biermann, Matan Hofree, Lindsay Caprio, Simon Berhe, Shaheer A. Khan, Brian S. Henick, Antoni Ribas, Evan Z. Macosko, Fei Chen, Alison M. Taylor, Gary K. Schwartz, Richard D. Carvajal, Elham Azizi, Benjamin Izar
Journal: Nature Genetics (2023)
Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study
Authors: Angela Genchi, Elena Brambilla, Francesca Sangalli, Marta Radaelli, Marco Bacigaluppi, Roberto Furlan, Annapaola Andolfo, Denise Drago, Cinzia Magagnotti, Giulia Maria Scotti, Raffaella Greco, Paolo Vezzulli, Linda Ottoboni, Marco Bonopane, Daniela Capilupo, Francesca Ruffini, Daniela Belotti, Benedetta Cabiati, Stefania Cesana, Giada Matera, Letizia Leocani, Vittorio Martinelli, Lucia Moiola, Luca Vago, Paola Panina-Bordignon, Andrea Falini, Fabio Ciceri, Anna Uglietti, Maria Pia Sormani, Giancarlo Comi, Mario Alberto Battaglia, Maria A. Rocca, Loredana Storelli, Elisabetta Pagani, Giuseppe Gaipa, Gianvito Martino
Journal: Nature Medicine (2023)

Abstract Innovative pro-regenerative treatment strategies for progressive multiple sclerosis (PMS), combining neuroprotection and immunomodulation, represent an unmet need. Neural precursor cells (NPCs) transplanted in animal models of multiple sclerosis have shown preclinical efficacy by promoting neuroprotection and remyelination by releasing molecules sustaining trophic support and neural plasticity. Here we present the results of STEMS, a prospective, therapeutic exploratory, non-randomized, open-label, single-dose-finding phase 1 clinical trial ( NCT03269071 , EudraCT 2016-002020-86), performed at San Raffaele Hospital in Milan, Italy, evaluating the feasibility, safety and tolerability of intrathecally transplanted human fetal NPCs ( hf NPCs) in 12 patients with PMS (with evidence of disease progression, Expanded Disability Status Scale ≥6.5, age 18–55 years, disease duration 2–20 years, without any alternative approved therapy). The safety primary outcome was reached, with no severe adverse reactions related to hf NPCs at 2-year follow-up, clearly demonstrating that hf NPC therapy in PMS is feasible, safe and tolerable. Exploratory secondary analyses showed a lower rate of brain atrophy in patients receiving the highest dosage of hf NPCs and increased cerebrospinal fluid levels of anti-inflammatory and neuroprotective molecules. Although preliminary, these results support the rationale and value of future clinical studies with the highest dose of hf NPCs in a larger cohort of patients.
Radiotheranostics in oncology: Making precision medicine possible
Authors: Eric O. Aboagye, Tara D. Barwick, Uwe Haberkorn
Journal: CA A Cancer Journal for Clinicians (2023)

Abstract A quintessential setting for precision medicine, theranostics refers to a rapidly evolving field of medicine in which disease is diagnosed followed by treatment of disease‐positive patients using tools for the therapy identical or similar to those used for the diagnosis. Against the backdrop of only‐treat‐when‐visualized , the goal is a high therapeutic index with efficacy markedly surpassing toxicity. Oncology leads the way in theranostics innovation, where the approach has become possible with the identification of unique proteins and other factors selectively expressed in cancer versus healthy tissue, advances in imaging technology able to report these tissue factors, and major understanding of targeting chemicals and nanodevices together with methods to attach labels or warheads for imaging and therapy. Radiotheranostics —using radiopharmaceuticals—is becoming routine in patients with prostate cancer and neuroendocrine tumors who express the proteins PSMA (prostate‐specific membrane antigen) and SSTR2 (somatostatin receptor 2), respectively, on their cancer. The palpable excitement in the field stems from the finding that a proportion of patients with large metastatic burden show complete and partial responses, and this outcome is catalyzing the search for more radiotheranostics approaches. Not every patient will benefit from radiotheranostics; but, for those who cross the target‐detected line, the likelihood of response is very high.
Improving Risk Stratification for Patients With Type 2 Myocardial Infarction
Authors: Caelan Taggart, Karla Monterrubio-Gómez, Andreas Roos, Jasper Boeddinghaus, Dorien M. Kimenai, Erik Kadesjo, Anda Bularga, Ryan Wereski, Amy Ferry, Matthew Lowry, Atul Anand, Kuan Ken Lee, Dimitrios Doudesis, Ioanna Manolopoulou, Thomas Nestelberger, Luca Koechlin, Pedro Lopez-Ayala, Christian Mueller, Nicholas L. Mills, Catalina A. Vallejos, Andrew R. Chapman
Journal: Journal of the American College of Cardiology (2023)

Despite poor cardiovascular outcomes, there are no dedicated, validated risk stratification tools to guide investigation or treatment in type 2 myocardial infarction. The goal of this study was to derive and validate a risk stratification tool for the prediction of death or future myocardial infarction in patients with type 2 myocardial infarction. The T2-risk score was developed in a prospective multicenter cohort of consecutive patients with type 2 myocardial infarction. Cox proportional hazards models were constructed for the primary outcome of myocardial infarction or death at 1 year using variables selected a priori based on clinical importance. Discrimination was assessed by area under the receiving-operating characteristic curve (AUC). Calibration was investigated graphically. The tool was validated in a single-center cohort of consecutive patients and in a multicenter cohort study from sites across Europe. There were 1,121, 250, and 253 patients in the derivation, single-center, and multicenter validation cohorts, with the primary outcome occurring in 27% (297 of 1,121), 26% (66 of 250), and 14% (35 of 253) of patients, respectively. The T2-risk score incorporating age, ischemic heart disease, heart failure, diabetes mellitus, myocardial ischemia on electrocardiogram, heart rate, anemia, estimated glomerular filtration rate, and maximal cardiac troponin concentration had good discrimination (AUC: 0.76; 95% CI: 0.73-0.79) for the primary outcome and was well calibrated. Discrimination was similar in the consecutive patient (AUC: 0.83; 95% CI: 0.77-0.88) and multicenter (AUC: 0.74; 95% CI: 0.64-0.83) cohorts. T2-risk provided improved discrimination over the Global Registry of Acute Coronary Events 2.0 risk score in all cohorts. The T2-risk score performed well in different health care settings and could help clinicians to prognosticate, as well as target investigation and preventative therapies more effectively. (High-Sensitivity Troponin in the Evaluation of Patients With Suspected Acute Coronary Syndrome [High-STEACS]; NCT01852123)
Survival After Septal Reduction in Patients &gt;65 Years Old With Obstructive Hypertrophic Cardiomyopathy
Authors: Amgad Mentias, Nicholas G. Smedira, Amar Krishnaswamy, Grant W. Reed, Susan Ospina, Maran Thamilarasan, Zoran B. Popovic, Bo Xu, Samir R. Kapadia, Milind Y. Desai
Journal: Journal of the American College of Cardiology (2023)